Microbes on the move: infectious diseases in asylum seekers: Screening and vaccination policies

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University of Groningen

Microbes on the move: infectious diseases in asylum seekers

Ravensbergen, Sofanne

DOI:

10.33612/diss.147006916

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Publication date: 2020

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Ravensbergen, S. (2020). Microbes on the move: infectious diseases in asylum seekers: Screening and vaccination policies. University of Groningen. https://doi.org/10.33612/diss.147006916

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COLOPHON

Cover design: James Jardine | www.jamesjardine.nl Layout: James Jardine | www.jamesjardine.nl Print: Ridderprint | www.ridderprint.nl

The work described within this thesis was financially supported by the University of Groningen Junior Scientifc Masterclass (MD/PhD JSM grant), the INTERREG V A (202085) funded project EurHealth-1Health (http://www.eurhealth1health. eu), part of a Dutch-German cross-border network supported by the European Commission, the Dutch Ministry of Health, Welfare and Sport, the Ministry of Economy, Innovation, Digitalisation and Energy of the German Federal State of North Rhine-Westphalia and the Ministry for National and European Affairs and Regional Development of Lower Saxony, the Jan Kornelis de Cock Foundation, the Gratama stichting, and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) through the ESCMID Study Group Research Funding.

Printing of this thesis was financially supported by the Graduate School of Medical Sciences of the University of Groningen and the University of Groningen library. This support is greatly appreciated.

unauthorized reprint or use of this material is prohibited. No parts of this thesis may be reproduced, stored or transmitted in any form or by any means, without written permission of the author or, when appropriate, of the publishers of the publications.

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Microbes on the move: infectious

diseases in asylum seekers

Screening and vaccination policies

P R O E F S C H R I F T

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen

op gezag van de

rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op woensdag 16 december 2020 om 14.30 uur

door

Sofia Jacobine Ravensbergen

geboren op 23 april 1992 te Rijnsburg

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Promotores

Prof. dr. Y. Stienstra Prof. dr. T. S. van der Werf

Copromotor

Dr. E. Bathoorn

Beoordelingscommissie

Prof. dr. J.M. van Dijl Prof. dr. M.J. Postma Prof. dr. W.J. Wiersinga

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Paranymfen

Margot Elisabeth Tamminga Arie Pieter Paulus Ravensbergen

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01

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General introduction

Recent migration trends

In 2011, the Syrian civil war started which led to turmoil and instability in Syria and the surrounding countries in the Middle East. The United Nations High Commissioner for Refugees (UNHCR) estimated that more than 5.7 million Syrian people fled the country and more than 6.1 million people have been displaced internally from 2011 up to date1_{. The Syrian conflict, but also continuous unrest in other areas in the}

Middle-East, Asia and Africa2,3_{, forced millions of people to flee their home land.}

During the last decades, the number of forcibly displaced people was estimated around 40 million people each year. In 2018, the population of forcibly displaced people grew up to 70.8 million3_{. This increase was most significant between 2012}

and 2015. Over 1 million people tried to reach Europe in 2015 alone. People mainly originated from Syria (4.9 million) and Afghanistan (2.7 million)4_{, leading to the}

highest increase of migration that Europe had faced since the Second World War. Nowadays, the number of refugees trying to reach Europe has declined compared to 2015. However, considering the political instability of areas like the Middle-East or Africa, the number of refugees will fluctuate in the years to come.

Migration and health care challenges

In an attempt to reach European shores, different routes are taken by refugees. The European Border and Coast Guard Agency, also known as Frontex, reported seven active routes, namely5_:

1. Eastern land borders 2. Western Balkan

3. Circular route from Albania to Greece 4. Black Sea

5. Central Mediterranean 6. Western Mediterranean 7. Eastern Mediterranean

The Western Mediterranean and Eastern Mediterranean route are considered as the most active routes at the moment and are reported to have the highest number of border crossings. In 2018, the numbers of border crossings reported for both routes are 57 034 and 56 561 respectively. Via the Western Mediterranean and the Eastern Mediterranean route, refugees mainly arrive in Spain and Greece while Italy has to deal with a high number of refugees trying to enter the country through the Central Mediterranean route. The Central Mediterranean route used to be one of the main migration routes to the European Union/European Economic Area (EU/

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12 Chapter 1

EEA). However, since the start of an active policy of the Libyan Coast Guard in the summer of 2017, the number of border crossings declined with 80%. In 2018, 23 485 border crossings were reported. This is the lowest number since 20126_.

Based on the Dublin regulation (regulation no. 604/2013), an EU Member State is obligated to evaluate asylum claims after arrival in Europe. This obligation generally attributes to the Member State that plays the most significant role after initial arrival in Europe and aims to guarantee a quick asylum procedure for every refugee7,8_{. In}

practice however, this results in an enormous responsibility in terms of registration of these people for receiving countries like Italy and Greece.

According to article 12 of the International covenant on Economic, Social and cultural Rights (ICESCR), every person is entitled to health care. This right is phrased as follows:

“the right of everyone to the enjoyment of the highest attainable standard of physical and mental health”.

The key to the right to health contains two aspects; freedom and entitlement. Freedom includes consensual and informed healthcare. Entitlement indicates the obligation of the state to provide adequate health services, protection, access to information and education and sexual and reproductive health-care services9_{. This}

poses a challenge for local health care systems and healthcare workers within Europe to provide adequate health services for everyone in order to fulfil this obligation. Besides the responsibility of every European member state to provide adequate health care levels, refugees also face multiple barriers that withhold them from accessing health care. Barriers that have been reported are mostly considered to be language and cultural differences, discrimination and costs10–12_{. Another}

challenge regarding healthcare for refugees is the fear of detection, detention or deportation after seeking medical treatment. However, barriers may vary from country to country10_.

Migration and multidrug-resistant organisms

Multidrug-resistant organisms (MDROs) are defined as organisms that are resistant to one or more agents in at least three or more antibiotic classes. Methicillin-resistant Staphylococcus aureus is always considered as an MDRO regardless of the co-resistance in other antibiotic classes13_{. The epidemiology of MDROs within European}

countries varies significantly14_{. A closer look into the epidemiology of MDROs within}

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(EARS-Net) reveals a striking difference regarding the prevalence of MDROs within the EU15_{. For example, a prevalence of 6.2% for extended-spectrum}

β-lactamase-producing Escherichia coli is found in the Netherlands compared to 29.5% in Italy. The prevalence of carbapenem resistant Klebsiella pneumonia in the Netherlands and in Greece is 0.5% and 64.7% respectively16_{. Travelling and migration are known}

factors in the spread of MDROs. The transnational journey and crowded conditions in refugee camps or settlements are considerable factors in the dispersion of antimicrobial resistance among this vulnerable group. Possible introduction of MDROs in Europe could have consequences for subsequent screening procedures that are needed in low prevalence countries like the Netherlands.

Migration and infectious diseases

Besides MDROs, migration may lead to the introduction of infectious diseases that medical professionals in Europe are less familiar with. As an example, in July 2015, a patient from Eritrea who just arrived in the Netherlands was admitted to a regional hospital in the northern Netherlands with complaints of headache and fever. Malaria was suspected but could not be diagnosed. The patient received ceftriaxone as empirical therapy. As a reaction the patient’s situation deteriorated within hours and the patient had to be admitted to the Intensive Care Unit at the University Medical Center Groningen (UMCG). Later, louse borne relapsing fever caused by Borrelia recurrentis was diagnosed17_{. A second case occurred only one week later, but was}

directly referred to the UMCG. Additional cases of louse borne relapsing fever were reported in Switzerland in August 201518_{and Italy in September 2015}19_{. In the}

following months, at least 40 confirmed Borrelia recurrentis cases were reported in Germany20_{, one case in Belgium}21_{, and two cases in Finland}22_{. The two cases in the}

UMCG initiated the work presented in this thesis. The patients demonstrated the urgency to further investigate infectious diseases observed in asylum seekers who are referred to the hospital.

In addition to the introduction of infectious diseases unfamiliar to European medical professionals, a second challenge in migrant health is the protection of migrants against infectious diseases. As migrants originate from countries where healthcare systems have been inadequate for years, vaccination rates are expected to be insufficient. An adequate tool to reduce the burden of infectious disease is to ensure adequate vaccination rates among migrants. In order to guarantee adequate vaccination rates, a European approach is needed to organize vaccination of migrants on a European level. Moreover, due to the crowded condition during their journey to Europe and in settlements, outbreaks of communicable diseases

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14 Chapter 1

also occur, mainly affecting unvaccinated migrants23–25_{. An example is a scabies}

outbreak in a settlement in Calais in 2014. Such outbreaks require a quick response to contain the outbreak now and in the future.

The asylum procedure in the Netherlands

The Netherlands has a centralized system of asylum requests. Apart from a small minority arriving at the national airport Schiphol, the majority of asylum seekers has to apply for asylum at the national registration centre of the Immigration and Naturalisation Service (IND). These centres are located in Ter Apel in the north-eastern part of the Netherlands or in Budel in the Southern part of the Netherlands. Asylum seekers stay for a maximum of 72 hours at the national registration centre. Here, the Aliens Police conducts an identity check and all personal data is registered. After registration, asylum seekers are screened for active pulmonary tuberculosis by the Public Health Service Groningen (GGD). Chest radiography is used as a standard screening tool in The Netherlands and is mandatory for all asylum seekers over six months old. Asylum seekers who originate from countries with a tuberculosis incidence of less than 50 cases per 100 000 inhabitants are excluded from the screening (e.g. asylum seekers originating from Syria)26,27_{. In}

case the chest X-ray is suggestive of intrathoracic tuberculosis, further diagnostic procedures are performed by the tuberculosis department of the regional Public Health Service Groningen, or by the UMCG. Eventually, treatment is started by the GGD Groningen or the UMCG. After 72 hours at the national reception centre, asylum seekers are transferred to one of the asylum centres in the Netherlands to wait for the processing of their asylum application.

Aims and outline of the thesis

The overall goal of the thesis is to improve the knowledge regarding the epidemiology of MDROs among asylum seekers and to evaluate current screening and vaccination procedures in the Netherlands and Europe. Therefore, the aim of the work presented in this thesis is twofold. Part I of this thesis aims to investigate the prevalence of MDROs in asylum seekers in the Netherlands, the duration of carriage of MDROs and the possible consequences for screening procedures. This introduction, Chapter 1, describes the migration trend over the last few years. It describes the challenges in the provision of health care for refugees and the asylum procedure in the Netherlands. Chapter 2 shows the prevalence of infectious diseases and MDROs from asylum seekers admitted to the UMCG. Chapter 3 provides more insight into the prevalence of MDROs in asylum seekers, focussing on the north-eastern part of the Netherlands. The prevalence of MDROs is compared to the

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prevalence of MDROs in the general patient population in the Netherlands. Chapter

4 discusses the duration of MDRO carriage in the asylum seeker population after

arrival in the Netherlands. Chapter 5 investigates if transmission or outbreaks of ESBL-producing Gram negative bacteria have occurred amongst asylum seekers either during the travel to Europe or during their stay in the asylum seeker centre by the use of whole genome sequencing.

Part II of this thesis focuses on different screening and vaccination programmes within the Netherlands and Europe. Chapter 6 evaluates the scabies programme that was introduced in the national reception center in Ter Apel in order to reduce the number of scabies cases reported. Chapter 7 describes the potential of mass drug administration to reduce the burden of scabies in refugee settings. Chapter 8 and Chapter 9 focus on the vaccination programmes for recently arrived refugees in the EU/EEA countries. First, a policy analysis is performed across all countries to compare national approaches. Subsequently, national experts across all EU/EEA countries completed a survey to evaluate current approaches on the vaccination of refugees. Chapter 10 aims to investigate refugees’ perspectives on infectious diseases screening and vaccination policies. Chapter 11 summarizes all the results of this thesis. Chapter 12 discusses the results and the future perspectives.

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16 Chapter 1

REFERENCES

1. Syrian Civil War Fast Facts - CNN. https://www.cnn.com/2013/08/27/world/meast/syria-civil-war-fast-facts/index.html. Published 2018. Accessed August 6, 2018.

2. Conflicts in Africa — Global Issues. http://www.globalissues.org/issue/83/conflicts-in-africa. Accessed September 3, 2018.

3. Global Trends - Forced Displacement in 2018 - UNHCR, the UN Refugee Agency. UNHCR. https://www.unhcr.org/globaltrends2018/. Published 2018. Accessed November 28, 2019.

4. United Nations High Commissioner of Refugees. UNHCR Global Trends 2015. http:// www.unhcr.org/statistics/unhcrstats/576408cd7/unhcr-global-trends-2015.html. Published 2016. Accessed May 23, 2017.

5. Frontex. Migratory Map. https://frontex.europa.eu/along-eu-borders/migratory-map/. Accessed December 11, 2018.

6. Central Mediterranean Route. https://frontex.europa.eu/along-eu-borders/migratory-routes/central-mediterranean-route/. Accessed August 6, 2018.

7. European Commission. Country responsible for asylum application (Dublin). European Commission Migration and Home Affairs. https://ec.europa.eu/home-affairs/what-we-do/policies/asylum/examination-of-applicants_en. Published 2017. Accessed August 6, 2018.

8. EUR-Lex - 32013R0604 - EN - EUR-Lex. https://eur-lex.europa.eu/legal-content/EN/ LSU/?uri=CELEX:32013R0604. Accessed August 6, 2018.

9. Krug Nygren H. International migration, health and human rights. Health and Human Rights. https://apps.who.int/iris/bitstream/handle/10665/42793/9241562536.pdf. Published 2013. Accessed August 9, 2017.

10. WHO – World Health Organization. Promoting the health of refugees and migrants: Draft global action plan, 2019–2023. Seventy-second WHA Provisional agenda item. 2019:1-13.

11. Chuah FLH, Tan ST, Yeo J, Legido-Quigley H. The health needs and access barriers among refugees and asylum-seekers in Malaysia: A qualitative study. Int J Equity Health. 2018;17(1).

12. Zeidan AJ, Khatri UG, Munyikwa M, Barden A, Samuels-Kalow M. Barriers to Accessing Acute Care for Newly Arrived Refugees. West J Emerg Med. 2019;20(6):842-850. 13. Magiorakos AP, Srinivasan A, Carey RB, et al. Multiresistant, extensively

drug-resistant and pandrug-drug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268-281. 14. European Commission. AMR: a major European and Global challenge. Health and Food

Safety. https://ec.europa.eu/health/amr/sites/health/files/antimicrobial_resistance/ docs/amr_2017_factsheet.pdf. Published 2017. Accessed September 28, 2019.

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15. Centre E, Prevention D. Data from the ECDC Surveillance Atlas - Antimicrobial resistance. https://ecdc.europa.eu/en/antimicrobial-resistance/surveillance-and-disease-data/data-ecdc. Published 2018. Accessed September 28, 2019.

16. Report S. Surveillance Report. https://ecdc.europa.eu/sites/portal/files/documents/ EARS-Net-report-2017-update-jan-2019.pdf. Published 2003. Accessed September 28, 2019.

17. Wilting KR, Stienstra Y, Sinha B, Braks M, Cornish D, Grundmann H. Louse-borne relapsing fever (Borrelia recurrentis) in asylum seekers from Eritrea, The Netherlands, July 2015. Eurosurveillance. 2015;20(30):21196.

18. Osthoff M, Schibli A, Fadini D, Lardelli P, Goldenberger D. Louse-borne relapsing fever - report of four cases in Switzerland, June-December 2015. BMC Infect Dis. 2016;16(1):210. 19. Antinori S, Mediannikov O, Corbellino M, et al. Louse-Borne Relapsing Fever (Borrelia

recurrentis) in a Somali Refugee Arriving in Italy: A Re-emerging Infection in Europe? Werneck GL, ed. PLoS Negl Trop Dis. 2016;10(5):e0004522.

20. Ackermann N, Marosevic D, Hörmansdorfer S, et al. Screening for infectious diseases among newly arrived asylum seekers, Bavaria, Germany, 2015. Eurosurveillance. 2018;23(10):00176.

21. Darcis G, Hayette MP, Bontems S, et al. Louse-borne relapsing fever in a refugee from Somalia arriving in Belgium. J Travel Med. 2016;23(3).

22. Hytönen J, Khawaja T, Grönroos JO, Jalava A, Meri S, Oksi J. Louse-borne relapsing fever in Finland in two asylum seekers from Somalia. APMIS. 2017;125(1):59-62.

23. French police clear hundreds of asylum-seekers from Calais migrant camps after outbreak of scabies | The Independent. http://www.independent.co.uk/news/world/ europe/french-police-clear-hundreds-of-asylum-seekers-from-calais-migrant-camps-after-outbreak-of-scabies-9444407.html. Accessed February 1, 2018.

24. Jones G, Haeghebaert S, Merlin B, et al. Measles outbreak in a refugee settlement in Calais, France: January to February 2016. Eurosurveillance. 2016;21(11):30167.

25. Lampl BMJ, Lang M, Pregler M, Zowe M, Beck R, Schonberger K. Management of a measles outbreak in a reception facility for asylum seekers in Regensburg, Germany. GMS Hyg Infect Control. 2019;14:Doc06.

26. De Vries G, Van Rest J, Meijer W, Wolters B, Van Hest R. Low yield of screening asylum seekers from countries with a tuberculosis incidence of <50 per 100000 population. Eur Respir J. 2016;47(6):1870-1872.

27. Akkerman OW, De Lange WCM, Schölvinck EH, et al. Implementing tuberculosis entry screening for asylum seekers: The Groningen experience. Eur Respir J. 2016;48(1):261-264.

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PART I

Multidrug-resistant organisms

in asylum seekers

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02

High Prevalence of Infectious Diseases

and Drug-Resistant Microorganisms in

Asylum Seekers Admitted to Hospital;

No Carbapenemase Producing

Enterobacteriaceae until September 2015

P LO S O N E . VO LU M E 1 1 , I S S U E 5 , E 0 1 5 4 7 9 1 ( 2 0 1 6 )

Sofanne J. Ravensbergen1_{, Mariëtte Lokate}2_{, Darren Cornish}3_{, Eveline Kloeze}1_,

Alewijn Ott2,4_{, Alex W. Friedrich}2_{, Rob van Hest}5_{, Onno W. Akkerman}6_{, Wiel}

C. de Lange6_{, Tjip S. van der Werf}1,6_{, Erik Bathoorn}2_{, Ymkje Stienstra}1

1 Department of Internal Medicine/Infectious Diseases, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands

2 Department of Medical Microbiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands

3 Primary Health Care Centre for Asylum Seekers (Gezondheidscentrum Asielzoekers), Ter Apel, The Netherlands 4 Department of Medical Microbiology, Certe, Groningen, The Netherlands

5 Department of Tuberculosis Control, Regional Public Health Service Groningen, Groningen, The Netherlands 6 Department of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Centre Groningen,

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ABSTRACT

Introduction

The current refugee crisis emphasizes the need for information on infectious diseases and resistant microorganisms in asylum seekers with possible consequences for public health and infection control.

Materials and Methods

We collected data from asylum seekers admitted to our university hospital or who presented at the Emergency Department (n=273). We collected general and demographic characteristics including country of origin, the reason of presentation, and the screening results of multidrug-resistant organisms (MDROs).

Results

67% of the patients were male with a median age of the study group of 24 years (IQR 15-33); 48% of the patients had an infectious disease – predominantly malaria with P. vivax or tuberculosis. Patients also reported with diseases which are less common - e.g. leishmaniasis, or even conditions rarely diagnosed in Europe – e.g. louse borne relapsing fever. A carriage rate of 31% for MDRO was observed, with ESBL-expressing E.coli (n=20) being the most common MDRO. No carriage of Carbapenemase Producing Enterobacteriaceae was found.

Conclusion

The current refugee crisis in Europe challenges hospitals to quickly identify and respond to communicable diseases and the carriage of MDRO. A rapid response is necessary to optimize the treatment of infectious diseases amongst asylum seekers to maximize infection control.

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High prevalence of infectious diseases and drug-resistant microorganisms in asylum seekers

INTRODUCTION

The current refugee crisis in Europe challenges both society as a whole and health care workers. Six hundred and twenty-six thousand people applied for asylum in the 28 European (EU) Member States in 2014. When compared to 2013, this was an increase of 45%1_{. More than 350,000 refugees reported at the EU borders between}

January-September 2015. This number may be an underestimate as many refugees may have remained undetected2,3_.

Next to travelling, migration is a well-known factor in the spread of infectious diseases and multidrug-resistant organisms (MDROs)4_{. However, little is known}

about the carriage of infectious diseases and MDRO in asylum seekers whenever they report with illness to the healthcare system in the host country with possible implications for hospital infection control.

The Netherlands have a very active surveillance for MDRO with a very low MDRO prevalence among patients admitted to hospital5_{. The overall carriage of extended}

spectrum beta-lactamase (ESBL) producing bacteria in the Dutch population is 5.1%6_.

In hospitals the overall carriage rate of vancomycin-resistant enterococci (VRE) is 0.4% and the percentage of methicillin-resistant Staphylococcus aureus (MRSA) is only 2%. Most cases of Carbapenemase-producing Enterobactereaceae (CPE) in the Netherlands have been reported in patients repatriated from a foreign hospital7_,

although some hospital outbreaks have occurred8_{. The Netherlands has a strict}

hospital infection prevention policy, especially with respect to screening for patient admissions for those recently admitted to hospitals in foreign countries. Screening policy does not include travellers and it is currently unclear whether asylum seekers without a recent hospital admission would need to be screened.

In addition to the carriage of MDRO, asylum seekers may present with infectious diseases which may have consequences for public health and hospital hygiene; immigrants are known to have a higher rate of tuberculosis compared to the indigenous population9,10_{. However rates may vary considerably between countries}

of origin. The incidence of tuberculosis is 78 per 100.000 inhabitants in Eritrea and 17 per 100.000 inhabitants in Syria11_{. Information on MDRO carriage in countries of}

origin is scarce. In Syria the rate of MDR gram negative bacteria in selected patient populations with clinical infections was around 50-60%12,13_.

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24 Chapter 2

The spectrum of infectious diseases asylum seekers present with depends on risk factors such as country of origin, exposure during travel, previous living conditions, and access to health care and migration routes14_.

Here we report the spectrum of infectious diseases, prevalence of patients carrying MDRO’s amongst asylum seekers who presented to the University Medical Centre Groningen which is located close to the national registration centre for asylum seekers in the Netherlands. Our data may conceivably help improve adequate care for asylum seekers with infectious diseases and enable optimal hospital hygiene strategies.

MATERIALS AND METHODS

Asylum seeking procedure in the Netherlands

In 2014 24,929 asylum seekers arrived in the Netherlands, an increase of almost 62% compared to 2013 (15,394). In the context of the current European refugee crisis, the number of asylum seekers in 2015 has increased considerably. Since January 2015 up until the beginning of September 2015, 33,598 asylum seekers had already reported at the national registration centre15_.

The Netherlands operate a centralised system of asylum application. Apart from a small minority at the national airport Schiphol and unaccompanied minors, the majority of asylum seekers must file their request at the national registration centre in Ter Apel. Within the first three days following arrival individuals are identified, registered and screened for active pulmonary tuberculosis. In Spring 2014 a standard preventative treatment of scabies was introduced. Screening is performed by the municipal health services. All asylum seekers are insured by the same insurance company and have an insurance number that starts with 9010 as decided by the insurance company. After this period, asylum seekers move to one of the asylum centres in the Netherlands to await processing16_.

Screening at admission to the hospital

The University Medical Centre Groningen is the university hospital closest to the national registration centre (60 km) and a preferred carrier for treating infectious diseases. The general practitioner based at the national registration centre decides whether the asylum seeker is referred to the regional hospital or the university hospital and for abnormalities found during TB screening the TB control physician in Groningen decides.

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General infection prevention policy in the Netherlands includes screening for MRSA, VRE and resistant gram-negative bacteria of all patients who admitted to a hospital outside the Netherlands in the past 2 months.

In April 2014, the department of medical microbiology in the UMCG advised screening for MRSA, VRE, and multidrug-resistant gram negatives for all asylum seekers admitted to the hospital or who presented at the emergency department (with a high probability of a subsequent admission). This advice was only given if admission or outpatient visit was reported. The reason for screening was the anticipated high carriage rate of MDRO in asylum seekers when considering their countries of origin. Asylum seekers who were admitted or presented to the emergency department were screened for carriage of the following MDRO’s: MRSA, ESBL, fluorquinolone- and aminoglycoside-resistant (MDR) Gram-negative bacteria, VRE, and CPE as part of standard care.

Carriage of MDRO does not have consequences for hospital hygiene measure in the outpatient setting. Therefore patients only visiting out-patient departments were not included in the MDRO screening.

Selection of participants

A retrospective study was conducted at the UMCG. All asylum seekers admitted to the UMCG or reporting to the emergency department between April 1st 2014 through September 1st 2015 were included. Patients were identified as asylum seekers based on their specific insurance number. Patients with the specific insurance number but whose asylum request was rejected by legal authorities as evidenced by the information available in their medical records were not included. Only asylum seekers who presented at the emergency department or who were admitted to the wards, or the tuberculosis department were included. If patients were admitted more than once, only the first admission in the study period was included.

General characteristics such as age at admission, gender, country of origin, and arrival data in the Netherlands, admission period and reason of admission were collected. Detailed information was collected concerning infectious conditions the patients presented with. The ICD-10 classification was used to describe the non-infectious diseases patients presented with at the hospital17_.

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26 Chapter 2

Screening for MDRO

Screening for MDRO consisted of swabs from nose, throat, rectum and perineum. MRSA was tested on nose, throat and perineum swabs with PCR (GeneXpert Cepheid). These swabs were also cultured on enrichment broth and chromID-MRSA plates (Biomerieux). VRE was detected as described previously 18_{. Presence}

of MDR Gram-negative bacteria in throat and rectum swabs was detected by culture on selective agar plates (3-com Iso sensitest agar ME/CF/CX and CI/TO/PT, Mediaproducts, Groningen, the Netherlands). Antibiotic susceptibility was tested by automated susceptibility testing (VITEK2, bioMerieux, Marcy l’Etoile, France), or E-tests (AB Biodisk, Mannheim, Germany) applying EUCAST guidelines. Presumptive ESBL-, plasmidal AmpC-, or carbapenemase-producing isolates were analysed for presence of resistance genes by a DNA-array (Check-MDR CT103, Check-points, Wageningen, The Netherlands).

If patients tested positive they were isolated during their stay in the hospital, according to national and local guidelines. All patients diagnosed with TB or some patients suspected to have TB are referred directly to the UMCG tuberculosis centre and sanatorium Beatrixoord. This facility serves as one of the two national referral centre’s for tuberculosis and is the largest designated tuberculosis centre in Europe. This study was evaluated by the ethics committee and was waived in accordance with Dutch legislation owing to its retrospective nature (University Medical Centre Groningen, METc number 2014/325). No written informed consent was obtained from patients for the use of retrospective data but patient information was anonymized and de-identified prior to analysis.

Statistical analysis

Data was collected in and analyzed with SPSS (version 2.22) and descriptive statistics were used for the diagnosis and MDRO screening results. Data is presented as mean (SD) or median with 25-75% inter quartile range (IQR) as appropriate. General data was obtained from the patients’ file. When the date of arrival was only mentioned the year, either the 1st_{July or 1}st_{of January was entered based on the information}

available.

The association between the number of days in the Netherlands and performing a screening for MDRO was calculated by Mann-Whitney-U test.

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RESULTS

Study population and group characteristics

Between April 1st 2014 through September 1st 2015 care was provided to 736 asylum seekers in our university hospital. We included 273 patients who presented at the emergency ward or were admitted to the ward for further analysis. General characteristics can be found in Table 1. Most people originated from Eritrea (36.5%) or Syria (18.6%). Thirty-three (12%) asylum seekers were babies born in the Netherlands.

TABLE 1. General characteristics of asylum seekers admitted or presenting at the emergency department Number of asylum seekers

Male (%) 184 (67%)

Days in the Netherlands Median (IQR)* 74 (22-247)

Age median (IQR) 24 (15-33)

Country of origin Eritrea (%) 92 (36.5) Syria (%) 47 (18.6) Afghanistan (%) 8 (3.2) Armenia (%) 21 (8.3) Nigeria (%) 7 (2.8) Other, Africa (%) 38 (15.1) Other, Asia (%) 21 (8.3)

Other, Middle East (%) 12 (4.8)

Other, Europe (%) 5 (2)

Other, South America (%) 1 (0.4)

Missing (%) 21 (8.3)

*In 153 patients, arrival date in the Netherlands had not been recorded

The median number of days in the Netherlands before presentation in the hospital was 74 (IQR 24-283). Many of the patients (32%) were admitted to the hospital or presented to the emergency department within the first 4 weeks after arrival in the Netherlands. Fourteen patients were admitted within the first week of arrival: 10

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28 Chapter 2

of whom were admitted within the first three days after arrival. In 56% (n=153) no arrival date was reported in the patient documentation. Patients were admitted for a median duration of 7 (IQR2-26) days.

Purpose of hospital visit

130 patients were admitted with an infectious disease of which 23% presented with vivax malaria (n=30) and 34% proved to have pulmonary tuberculosis (n=44). Three patients with pulmonary tuberculosis had drug resistant tuberculosis: one patient with MDRTB (from Georgia), one patient with XDRTB (from Latvia) and one patient with INH resistant pulmonary tuberculosis who originates from Syria but lived in both the Ukraine and Libya before seeking asylum in the Netherlands. 186 patients presented with non-infectious disease, with 22% (n=40) associated with pregnancy, childbirth and post-partum care, 11 % (n=22) with diseases of the circulatory system and 12 % with injury, poisoning and other consequences of external cause (n=21). The diseases asylum seekers presented with are described in detail in Table 2. Eleven admitted patients were coinfected with HIV.

Multidrug-resistant 0rganisms

Of the 130 patients tested, 31% (n=40) had one or more MDRO cultured, in total 52 MDROs. ESBL expressing E. coli (n=20) was the most common MDRO. Additionally four K. pneumoniae and one M. morganii and one E. cloacae were found ESBL positive. Thirteen from the 26 ESBL positive Enterobacteriaceae were resistant to fluoroquinolones and at least one of the aminoglycosides (both tobramycin and gentamicin were tested). Genes encoding for M-1-like, CTX-M-15-like, and CTX-M-9 group ESBLs were detected in 13 (50%), 6 (23%), and 5 (19%) isolates, respectively. SHV 238S/240K was detected in one isolate. In one isolate with ESBL phenotype no resistance genes were detected by DNA array. Sixteen Enterobacteriaceae (mainly E. coli) were resistant to aminoglycosides and fluoroquinolones without ESBL. One E. coli isolate was resistant to colistin. No carbapenemase-producing Enterobacteriaceae were found. With respect to gram positive MDROs, only ten patients were found to carry MRSA.

MDRO carriage appeared to be higher among people from Syria than from Eritrea (7/13 vs 14/64, RR 2.46 (95% CI: 1.24 – 4.88)). Carriage of an MDRO was significantly associated with a shorter duration of stay in the Netherlands: median days in the Netherlands of those with MDRO was 26 (IQR: 4-87) days versus those without MDRO 85 (IQR: 27-316) days, P<0.001. No MDRO was cultured in asylum seekers’ babies born in the Netherlands (n=9).

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TABLE 2. Purpose of visit; infectious and non-infectious diseases

Number (%) Infectious diseases

Bacterial; pulmonary tuberculosis (n= 44), suspected tuberculosis (n=9) intestinal tuberculosis (n=1), tuberculous peritonitis (n=1), relapsing fever Borrelia recurrentis (n=2)

57 (43.8) Parasitic; malaria (P. vivax n=28, P. falciparum n=2),

leishmaniasis (n=1), schistosomiasis (n=2), (scabies n=7) 40 (30.8)

Clinical presentation of an infection, not otherwise specified; fever, diarrhoea, abscess, respiratory infection, perinatal infection, deep infection of the finger, viral infection, tonsillitis, gastroenteritis, pharyngitis, eosinophilia

17 (13.1) Viral; viral bronchiolitis (n=2), viral respiratory infection (n=1), hepatitis C (n=9),

cytomegalovirus (n=1), disseminated Varicella Zoster Virus infection (n=2) 15 (11.5)

Fungus; nasopharyngeal candida 1 (0.8)

Total 130 (100)

Non infectious diseases

pregnancy, childbirth and the puerperium 40 (21.5)

injury, poisoning and certain other consequences of external causes 23 (12.4)

diseases of the circulatory system 22 (11.8)

certain conditions originating the perinatal period 19 (10.2)

genitourinary system 14 (7.5)

diseases of the nervous system 12 (6.4)

endocrine, nutritional and metabolic diseases 9 (4.8)

external causes of morbidity and mortality 8 (4.3)

diseases of the musculoskeletal system and connective tissue 5 (2.7)

diseases of the digestive system 5 (2.7)

diseases of the blood and immune system 5 (2.7)

diseases of the eye and adnexa 4 (2.1)

diseases of the ear and mastoid process 4 (2.1)

congenital malformations, deformations and chromosomal abnormalities 4 (2.1)

Neoplasms 4 (2.1)

mental and behavioural disorders 4 (2.1)

diseases of the respiratory system 3 (1.6)

diseases of the skin and subcutaneous tissue 3 (1.6)

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30 Chapter 2

DISCUSSION

Around half of the asylum seekers admitted at our university hospital presented with an infectious condition. The carriage rate of MDRO in asylum seekers was 31%. Carriage rate varied by the patients’ country of origin and the duration of stay in the Netherlands, however, no CPE was detected.

Given the number of asylum seekers presenting at the national registration centre in Ter Apel, up to 800 daily, the number of admitted patients or patients referred to the emergency department at our university medical centre was low considering the likely adverse conditions during transit.

The most common infectious diseases patients presented with in our hospital were tuberculosis and P. vivax malaria. An increase in P. vivax malaria in newly arrived Eritrean asylum seekers has been noticed before in Sweden and Norway and its increase seems related to the migration route19_.

The high number of tuberculosis patients in our study results both from a higher incidence in many countries of origin, from the screening by X-ray at arrival in the national reception centre in Ter Apel, and from the asylum seekers with tuberculosis referred by other hospitals in the Netherlands to the UMCG tuberculosis centre. Patients also presented with diseases that are less common such as leishmaniasis or even more seldomly diagnosed in Europe such as the LBRF. After the two patients who reported to our hospital with LBRF20_{additional patients were reported in}

Switzerland21_{and Germany}22_{. Because of the short incubation period the infection is}

likely to present quickly after arrival and thus at hospitals near to the single national registration centre.

Knowledge about infectious diseases and carriage of MDRO’s in asylum seekers is urgently needed to provide adequate care and to enable optimal hospital hygiene strategies. The carriage of MDRO in asylum seekers is high when compared to the Dutch population and also correlates to the carriage rate in country of origin as expected. Asylum seekers have a carriage rate of resistant Enterobacteriaceae comparable to Dutch inhabitants travelling abroad who are similarly known to import multidrug-resistant pathogens. Travellers from the Netherlands showed a high carriage rate of 30.5% of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) after their return from Asia, Africa or South America23_.

It should be considered whether screening policies should not only focus on asylum seekers, but also to consider screening Dutch patients admitted after

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international travels to Asia, Africa or South America as well. As an important fact, no CPE was found in asylum seekers. This is different to expectation, as regions of surrounding the country of origin of the asylum seekers are reported to have high prevalence of CPE24_{. As the prevalence of CPE is rising in other European}

countries, especially in South Europe, but also Germany, asylum seekers that have been treated in hospitals in those countries might get colonized during their travel to the Netherlands. Screening activities needs to be enhanced in order to identify CPE-carriers early. A recent study from Germany showed CPE-carriers and found a multidrug-resistant Gram-negative bacteria carriage rate of almost 61%25_which

is much higher than the MDRO carriage rate in our study. A higher background rate of MDRO in Germany, differences in travel routes and origin of asylum seekers and morbidity on admission, may all have contributed to the difference in MDRO carriage rate.

The aim of this study was to identify and list infectious diseases and carriage of high-risk potential pathogens that may have consequences for public health and infection control. We did not describe details of the non-communicable diseases asylum seekers presented with even though we realize that treatment of these non-communicable diseases are challenging considering the need of optimal compliance and follow-up26_.

The selection of asylum seekers in our hospital based on the insurance number is practical and ensures a complete selection of study participants. Selection based on information in the medical files is likely to be incomplete and selection based on the patients’ address leads to exclusion of asylum seekers do not live in the asylum centres or who have been transferred to other centres. The geographical location close to the single national registration centre ensures a true reflection of infectious diseases entering the Netherlands, especially considering the short incubation period from some of the infectious diseases.

Only the diagnoses at admissions were included because of their immediate importance for hospital hygiene measures. Purpose of visits to the out-patient clinic was not reported in this study. Psychiatric disorders are common in asylum seekers27_{. In our study, only four patients were admitted due to psychiatric disorders.}

However, most likely this low number does not reflect the actual prevalence; most frequently, in the Netherlands, these patients are referred to specialised regional units for transcultural psychiatry.

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32 Chapter 2

Another limitation to the study is the percentage of asylum seekers screened at admission. Screening of admitted asylum seekers or asylum seekers presenting at the emergency department was only partially implemented and as a result screening was only done in 48% of the patients. Additional screenings is needed to identify the risk factors for carriage of MDRO strains. These additional screenings will also provide more details on the antimicrobial resistance. Further typing of the MDRO may provide information on the likely route of transmission.

In conclusion, asylum seekers frequently present with infectious diseases, of which many have consequences for infection control. Hospital staff should be prepared to recognize uncommon, poverty-related infectious diseases, especially in hospitals seeing patients who have recently arrived in the Netherlands. A close collaboration with the municipal health centres and the general practitioners at the asylum centres enables a rapid response to new events. Screening for MDRO at admission is necessary at least for originating countries with a high background rate of MDRO to enable the optimal treatment for patients and optimal strategy for infection control.

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REFERENCES

1. European Commission. The number of asylum applicants in the EU jumped to more than 625 000 in 2014. https://ec.europa.eu/eurostat/documents/2995521/6751779/3-20032015-BP-EN.pdf/35e04263-2db5-4e75-b3d3-6b086b23ef2b. Published 2015. Accessed September 19, 2015.

2. BBC. Why is EU struggling with migrants and asylum? Bbc. https://www.bbc.com/news/ world-europe-24583286. Published 2016. Accessed September 19, 2015.

3. Mediterranean Migrant Arrivals Reach 20,484, Deaths: 525 | International Organization for Migration. 2015. https://www.iom.int/news/mediterranean-migrant-arrivals-deaths-sea-soar. Accessed September 19, 2015.

4. Van der Bij AK, Pitout JDD. The role of international travel in the worldwide spread of multiresistant enterobacteriaceae. J Antimicrob Chemother. 2012;67(9):2090-2100. 5. Van De Sande-Bruinsma N, Grundmann H, Verloo D, et al. Antimicrobial drug use and

resistance in Europe. Emerg Infect Dis. 2008;14(11):1722-1730.

6. Huijbers PMC, de Kraker M, Graat EAM, et al. Prevalence of extended-spectrum β-lactamase-producing Enterobacteriaceae in humans living in municipalities with high and low broiler density. Clin Microbiol Infect. 2013;19(6):E256-9.

7. NethmapMaran2015_webversie.pdf. http://www.swab.nl/swab/cms3.nsf/uploads/4F 5A0D8E6F0DD139C1257E6E0051833A/$FILE/NethmapMaran2015_webversie.pdf. Accessed September 15, 2019.

8. Glasner C, Albiger B, Buist G, et al. Carbapenemase-producing Enterobacteriaceae in Europe: A survey among national experts from 39 countries, February 2013. Eurosurveillance. 2013;18(28):20525.

9. Greenaway C, Sandoe A, Vissandjee B, et al. Tuberculosis: Evidence review for newly arriving immigrants and refugees. CMAJ. 2011;183(12):E939–51.

10. Lee D, Philen R, Wang Z, et al. Disease surveillance among newly arriving refugees and immigrants--Electronic Disease Notification System, United States, 2009. MMWR Surveill Summ. 2013;62(7):1-20.

11. World Health Organisation. Incidence of tuberculosis (per 100,000 people) | Data. The World Bank. https://data.worldbank.org/indicator/SH.TBS.INCD. Published 2015. Accessed September 15, 2019.

12. Teicher CL, Ronat JB, Fakhri RM, et al. Antimicrobial drug– resistant bacteria isolated from Syrian war–injured patients, August 2011–march 2013. Emerg Infect Dis. 2014;20(11):1949-1951.

13. Pfortmueller CA, Schwetlick M, Mueller T, Lehmann B, Exadaktylos AK. Adult asylum seekers from the middle east including Syria in central Europe: What are their health care problems? Correa-Velez I, ed. PLoS One. 2016;11(2):e0148196.

14. Pottie K, Greenaway C, Feightner J, et al. Evidence-based clinical guidelines for immigrants and refugees. Can Med Assoc J. 2011;183(12):e824-e925.

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34 Chapter 2

15. Feiten_en_Cijfers. https://www.coa.nl/nl/over-coa/feiten-en-cijfers. Accessed September 15, 2019.

16. Medische zorg vreemdelingen. https://www.nationaleombudsman.nl/uploads/2013-125_ rapport_medische_zorg_vreemdelingen_webversie_0.pdf. Published 2013. Accessed September 15, 2019.

17. ICD-10 Version:2015. https://icd.who.int/browse10/2015/en. Accessed September 15, 2019.

18. Zhou X, Arends JP, Kampinga GA, et al. Evaluation of the Xpert vanA/vanB assay using enriched inoculated broths for direct detection of vanB vancomycin-resistant enterococci. J Clin Microbiol. 2014;52(12):4293-4297.

19. Sondén K, Castro E, Trönnberg L, Stenström C, Tegnell A, Färnert A. High incidence of Plasmodium vivax malaria in newly arrived Eritrean refugees in Sweden since may 2014. Eurosurveillance. 2014;19(35):20890.

20. Wilting KR, Stienstra Y, Sinha B, Braks M, Cornish D, Grundmann H. Louse-borne relapsing fever (Borrelia recurrentis) in asylum seekers from Eritrea, The Netherlands, July 2015. Eurosurveillance. 2015;20(30):21196.

21. Goldenberger D, Claas GJ, Bloch-Infanger C, et al. Louse-borne relapsing fever (Borrelia Recurrentis) in an Eritrean refugee arriving in Switzerland, August 2015. Eurosurveillance. 2015;20(32):21204.

22. Diseases IS for I. Promed Post – ProMED-mail. 20191113.6774475. https://promedmail. org/promed-post/?id=20150911.3638819. Published 2019. Accessed September 15, 2019.

23. Paltansing S, Vlot JA, Kraakman MEM, et al. Extended-spectrum β-lactamase-producing enterobacteriaceae among travelers from the Netherlands. Emerg Infect Dis. 2013;19(8):1206-1213.

24. Djahmi N, Dunyach-Remy C, Pantel A, Dekhil M, Sotto A, Lavigne JP. Epidemiology of carbapenemase-producing enterobacteriaceae and acinetobacter baumannii in Mediterranean countries. Biomed Res Int. 2014;2014:305784.

25. Reinheimer C, Kempf VAJ, G?ttig S, et al. Multidrug-resistant organisms detected in refugee patients admitted to a University Hospital, Germany June-December 2015. Euro Surveill Bull Eur sur les Mal Transm = Eur Commun Dis Bull. 2016;21(2):30110.

26. Norredam M, Mygind A, Krasnik A. Access to health care for asylum seekers in the European Union - A comparative study of country policies. Eur J Public Health. 2006;16(3):285-289.

27. Gerritsen AAM, Bramsen I, Devillé W, van Willigen LHM, Hovens JE, van der Ploeg HM. Physical and mental health of Afghan, Iranian and Somali asylum seekers and refugees living in the Netherlands. Soc Psychiatry Psychiatr Epidemiol. 2006;41(1):18-26.

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03

High prevalence of MRSA and ESBL

among asylum seekers in the Netherlands

P LO S O N E . VO LU M E 1 2 , I S S U E 4 , E 0 1 7 6 4 8 1 ( 2 0 1 7 )

Sofanne J. Ravensbergen1_{, Matthijs Berends}2_{, Ymkje Stienstra}1_{, Alewijn Ott}2,3

1 Department of Internal Medicine/Infectious Diseases, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands,

2 Department of Medical Microbiology, Certe, Groningen, the Netherlands,

3 Department of Medical Microbiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands

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38 Chapter 3

ABSTRACT

Migration is one of the risk factors for the spread of multidrug-resistant organisms (MDROs). The increasing influx of migrants challenges local health care systems. To provide evidence for both hospital hygiene measure and empirical antibiotic therapy, we analysed all cultures performed in asylum seekers between January 1st_{2014 and}

December 31st_{2015 for methicillin resistant Staphylococcus aureus (MRSA) and for}

multidrug-resistant Enterobacteriaceae (MDRE). We compared these with cultures from the Dutch patient population with risk factors for carriage of MDRO. A total of 7181 patients were screened for MRSA. 7357 S. aureus were isolated in clinical cultures. Of 898 screened asylum seekers, almost 10% were MRSA positive. Of 118 asylum seekers with S. aureus in clinical cultures almost 19% were MRSA positive. The general patient population had a 1.3% rate of MRSA in S. aureus isolates. A higher rate of Panton-Valentine leukocidin (PVL) positive strains (RR: 2.4; 95% CI: 1.6-3.4) was found in asylum seekers compared to the general patient population. In 33475 patients one or more Enterobacteriaceae were obtained. More than 21% of the asylum seekers were carrier of MDRE, most of them producing extended spectrum beta-lactamases (20.3%). 5.1% of the general patient population was MDRE carrier. It can be concluded that asylum seekers present with higher rate of MDRO compared to the general patient population. These results justify continued screening of asylum seekers to anticipate multidrug-resistant organisms during hospital care of patients.

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High prevalence of MRSA and ESBL among asylum seekers in the Netherlands

INTRODUCTION

The Netherlands has a low prevalence of multidrug-resistant organisms (MDROs) compared to other countries in Europe. For example, the proportion of invasive methicillin resistant Staphylococcus aureus (MRSA) isolates in the Netherlands is less than 1% compared to more than 10% in surrounding countries like Belgium and Germany. Rates up to 37-56% are found in Greece, Portugal and Romania in 20141_.

To prevent transmission of MRSA, the Netherlands uses a “search and destroy” policy2_{. This policy includes screening of patients from high risk groups, strict}

isolation at admission of patients suspected to be colonized with MRSA until cultures are shown to be negative, but also eradication treatment of MRSA3–5_{. This strategy}

was proven to be cost-effective and results in less death due to a bacteraemia6_.

High risk groups include patients who were admitted to hospitals in foreign countries within the last two months. However, optimal screening policy for travellers and asylum seekers is unclear. International travel is considered as a risk factor for acquisition of MDROs like extended spectrum beta-lactamases (ESBL) or carbapenemase-producing Enterobacteriaceae (CPE)7_{. We reported a 31% carriage}

rate of multidrug-resistant microorganisms, with ESBL-expressing Escherichia coli being the most common in asylum seeker patients admitted in a tertiary care University hospital in The Netherlands8_{. However, only a limited number of asylum}

seekers were screened and these patients may not have been representative for the total asylum seekers’ population.

Asylum seekers arriving in The Netherlands originate mainly from Syria, Iraq, Afghanistan and Eritrea9_{. These countries are assumed to have a higher carriage}

rate of MDRO10,11_{. Due to the sudden high influx of asylum seekers and their expected}

higher carriage rate of MDRO, Dutch hospitals adopted various screening policies for MDRO in asylum seekers. A national screening policy is not available yet. More knowledge on MDRO carriage is needed to support decision making in national policies on hospital hygiene measures and empirical antibiotic therapy.

In this article, we will describe the rate of MRSA and multidrug-resistant Enterobacteriaceae (MDRE) among asylum seeker patients compared to the general patient population, based upon clinical and screening samples. This information may help to provide the best treatment and screening strategy for asylum seekers.

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40 Chapter 3

MATERIALS AND METHODS

The asylum procedure and medical care for asylum seekers

Due to the centralised system of asylum application that is operated by the Netherlands, almost all asylum seekers have to report their arrival at the national reception centre in the north-eastern province of Groningen. A minority reports at the national airport Schiphol. In the national registration centre, asylum seekers are registered and screened for active pulmonary tuberculosis by an X-ray. If (acute) medical care is needed, the patient is treated by the general practitioner at the national registration centre. If more specialised care is needed, the patient is referred to one of the regional hospitals.

The Certe laboratory

The Certe laboratory performs microbiological diagnostics for both general (primary) and specialised (hospital based) health care for a catchment population of about one million inhabitants in the north-east of the Netherlands. Since asylum seekers start their asylum procedure at the central organ for accommodating asylum seekers (COA) in this part of the Netherlands, the majority of samples taken in clinical care from asylum seekers who recently arrived in the country are sent to the Certe laboratory. For both asylum seekers and the general patient population about two third of all diagnostic samples come from one of the nine hospitals in the region. The remainder comes from primary care practitioners. Therefore, samples ranging from first to tertiary care are included.

Selection of participants

A retrospective analysis was performed at the Certe laboratory. The study period and study population were defined by all routine cultures processed between January 1st_{2014 and December 31}st_2015.

Asylum seekers (and their offspring) were identified by their address if they were living in one of the asylum centres (COAs) in the region. A few asylum seekers living outside the COA were identified because the culture request was done by the physician at the COA health centre. All other patients in the laboratory database were categorised as the “general patient population”.

Much care was taken to clear double entries of asylum seekers from the database. Duplication had occurred in around 3% of cases due to different spellings of names and (rarely) a wrong date of birth. In the general patient population, duplication

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is prevented by a citizen service number which is unique for all citizens in the Netherlands. It should be noted that the general patient population in this study includes immigrants, temporary residents from abroad and ex-asylum seekers after receiving their residence permit.

This study was evaluated by the ethics committee and was waived in accordance with Dutch legislation owing to its retrospective nature (University Medical Centre Groningen, METc number 2016/516). No written informed consent was obtained from patients for the use of retrospective data but patient information was anonymized and de-identified prior to analysis.

Methicillin Resistant Staphyloccus Aureus

MRSA was detected both actively and passively. Screening of patients for MRSA carriage can be regarded as an active method of detection whereas passive detection occurs in S. aureus isolates from clinical cultures performed to diagnose possible infection.

Screening was not done routinely in all asylum seekers, but most hospitals in the region adopted a screening regimen starting from April 2014. MRSA screening included a nasal, throat, perineum and only in some occasions skin culture. Most asylum seekers were screened in case of (anticipated) admission to the hospital. Additionally to screening, all S. aureus isolated from clinical cultures were included in the analyses to study the difference in MRSA prevalence between asylum seeker patients and the general patient population.

Culture swabs collected from patients were transported in clear Amies media and all processed within one day after collection. Clinical cultures were incubated on two to six non-selective media, depending upon possible infectious agents, always including staphylococci and enterobacteriaceae. For screening cultures we used selective media. In case of MRSA screening we incubated a blood agar (Mediaproducts BV) for growth control, a selective Chrom ID MRSA (bioMérieux) and a Mueller Hinton broth with NaCl 2.5% (Mediaproducts BV). The selective broth was subcultured on solid media after one night incubation. Growth of S. aureus was confirmed by Staphaurex Plus (Oxoid), coagulase-test and Martineau gene PCR. Antibiotic susceptibility of S. aureus was tested with the Vitek 2 automated system (bioMérieux). Isolates were additionally screened for beta-lactam resistance using the cefoxitin disk diffusion test12_{and MRSA confirmation was completed by detecting}

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42 Chapter 3

Of MRSA isolates the presence of the Panton-Valentine leukocidin (PVL) gene was tested with PCR. The PVL cytotoxin is associated with increased virulence of S. aureus. It is particularly associated with skin and soft tissue infections13_{. Molecular}

typing of MRSA isolates was done using Multiple Loci Variable Number Tandem Repeat Analysis (MLVA) performed by the Netherlands National Institute for Public Health and the Environment, which functions as the Dutch national reference centre for MRSA. The Multilocus sequence typing (MLST) clonal complex can be derived from most MLVA types.

Multidrug-resistant Enterobacteriaceae

Similarly as for MRSA, MDRE can be detected both actively and passively. All Enterobacteriaceae isolated from clinical cultures were selected. As for MRSA routine MDRE screening of asylum seekers, started only halfway the study period. MDRE screening was performed using rectal swabs, which were processed within one day after collection. A growth control on blood agar and three selective solid media, a McConkey with ciprofloxacin 0,5 mg/l and gentamicin 2 mg/l (Mediaproducts BV), a ChromID ESBL and a ChromID Carbapenemase agar (both bioMérieux) were incubated.

Three patterns of MDRE were distinguished: Extended Spectrum Beta-Lactamase (ESBL), Fluoroquinolone plus Aminoglycoside Resistant Enterobacteriaceae (QARE) and carbapenemase-producing Enterobacteriaceae (CPE). Suspicious colonies were identified on species level by using MALDI-TOF. Only after a correct and plausible identification, the antibiotic susceptibility of Enterobacteriaceae was tested with the Vitek 2 system.

The antibiotic susceptibility of Enterobacteriaceae was tested with the Vitek 2 system. Presence of ESBL was confirmed with cefotaxime-clavulanate, ceftazidime- clavulanate and cefepime-clavulanate E tests (bioMérieux)14_{. Possible CPE was}

confirmed by PCR (Check-Points, Check-MDR CT102).

Statistical analysis

Data were collected and analysed using Microsoft Excel and SPSS (version 2.22). Differences in proportions were tested for significance by Pearson’s uncorrected chi-squared test or the Fisher’s exact test as appropriate. Relative risk ratios (95% CI) were calculated for the virulence factor PVL and the MDRO rate.

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RESULTS

In total 1071 asylum seekers were included in the study of which 973 had MRSA screening cultures or S.aureus in one or more clinical cultures and 859 had MDRE screening cultures or at least one of the enterobacteriaceae in clinical cultures. Of these 1071 asylum seekers 545 had cultures submitted to the laboratory by a primary care worker and 627 had cultures done by the second line (hospital) care.

Methicillin Resistant Staphylococcus Aureus

During the study period 898 asylum seekers were actively screened for MRSA with a total of 3,106 cultures. Of these patients 87 (9.7%) were found to carry MRSA. In these patients MRSA was most often detected in their throat cultures (53; 61%), followed by nasal cultures (50; 57%) and perineum cultures (43; 49%).

In the same period 133 clinical cultures of 118 asylum seekers were positive with S. aureus isolates. Of these patients 22 (18.6%) carried MRSA (Table 1). 30.3% of the clinical isolates was a pus sample. No MRSA was obtained from blood cultures. Of the general patient population 66 individuals were excluded from analyses because they had been identified with MRSA before 2014. Screening for MRSA in the general patient population was mainly done in persons at increased risk of MRSA carriage or in case of a contact investigation. In brief, patients considered to have an increased risk are patients working with livestock and patients who have been admitted to a foreign hospital over the last 2 months. More detailed information on risk factors for which screening on MDRO is performed in the Netherlands can be found in the national guidelines3_.

By screening, 177 new MRSA carriers were found in patients from the general patient population. A lower number of MRSA was found in patients with infections; in the clinical cultures from the general patient population only 92 new patients with MRSA were found (Table 1).

Both screening and clinical cultures of asylum seekers were significantly more often MRSA positive than of the general patient population (p < 0.001).

Each unexpected finding of MRSA in a clinical culture of an admitted patient was followed by screening of all contacts of this patient (including both caretakers and patients). Hospital acquired MRSA was defined as MRSA found in case of contact tracing around an index patient and if both index and contact strains were similar.

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44 Chapter 3

According to that definition 25 of the 269 (9%) MRSA positive general patient (or caretaker) population had a hospital acquired MRSA, compared to one (1%) of the MRSA positive asylum seekers’ population.

TABLE 1. Results of MRSA screening and MRSA among S. aureus isolates cultured from clinical samples,

during 2014 – 2015, at the Certe laboratory.

Number of

patients Number with MRSA % with MRSA MRSA screening

General patient population* 6283 177 2.8%

Asylum seekers 898 87 9.7%

S. aureus in clinical samples

General patient population 7239 92 1.3%

total from screening and clinical samples**

General patient population 12989 269 2.1%

* screened at hospital admission because of increased risk of MRSA carriage or contact investigation ** 533 of the general patient population and 43 asylum seekers had both screening and clinical cultures (number of totals less than sum of screening and clinical samples).

MRSA genotyping

MRSA strains of asylum seekers were significantly more often PVL positive (42.0%) than of the general patient population (17.8% (RR: 2.4; 95% CI:1.6-3.4)). A high proportion (47.2%) of MRSA in the general patient population was livestock associated: CC398 or MLVA complex MC2236. This type of MRSA was never PVL positive. None of the asylum seekers had a livestock associated MRSA. After excluding livestock associated MRSA, 33.8% of the remaining general population patients’ MRSA was PVL positive, still lower than the proportion of PVL in asylum seekers’ MRSA, but this difference is not statistically significant (p = 0.19).

CC398 was by far the most common type of MRSA among the general patient population. In asylum seekers MRSA CC1 was the most prevalent type and 18 (66.7%) of these strains were PVL positive. CC5, CC8 and CC22 were isolated in both patient categories, but CC22 significantly more often in asylum seekers (p < 0.001). CC8 was evenly distributed in both groups, but remarkably none of the

Microbes on the move: infectious diseases in asylum seekers: Screening and vaccination policies

University of Groningen

Microbes on the move: infectious diseases in asylum seekers

Ravensbergen, Sofanne

COLOPHON

Microbes on the move: infectious

diseases in asylum seekers

Screening and vaccination policies

CONTENTS

01

REFERENCES

PART I

Multidrug-resistant organisms

in asylum seekers

02

High Prevalence of Infectious Diseases

and Drug-Resistant Microorganisms in

Asylum Seekers Admitted to Hospital;

No Carbapenemase Producing

Enterobacteriaceae until September 2015

ABSTRACT

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

REFERENCES

03

High prevalence of MRSA and ESBL

among asylum seekers in the Netherlands

ABSTRACT

INTRODUCTION

MATERIALS AND METHODS

RESULTS